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 Mephedrone Critical Review Report Agenda item 4.12 Expert Committee on Drug Dependence Thirty‐sixth Meeting Geneva, 16‐20 June 2014 36th ECDD (2014) Agenda item 4.12 Page 2 of 34 Mephedrone 36th ECDD (2014) Agenda item 4.12 Mephedrone Acknowledgements This report has been drafted under the responsibility of the WHO Secretariat, Essential
Medicines and Health Products, Policy Access and Rational Use Unit. The WHO Secretariat
would like to thank the following people for their contribution in producing this critical
review report: Wim Best, the Netherlands (literature review and drafting), Dr Caroline
Bodenschatz, Switzerland (editing) and Mr David Beran, Switzerland (questionnaire report
drafting).
Page 3 of 34 36th ECDD (2014) Agenda item 4.12 Page 4 of 34 Mephedrone 36th ECDD (2014) Agenda item 4.12 Mephedrone Contents Summary..............................................................................................................................................................................7
1.
Substance identification ............................................................................................................................................8
A.
B.
C.
D.
E.
F.
G.
2.
International Nonproprietary Name (INN) ........................................................................................................8
Chemical Abstract Service (CAS) Registry Number ..........................................................................................8
Other Names ........................................................................................................................................................8
Trade Names........................................................................................................................................................8
Street Names ........................................................................................................................................................8
Physical properties ..............................................................................................................................................8
WHO Review History ..........................................................................................................................................8
Chemistry ....................................................................................................................................................................8
A.
B.
C.
D.
E.
F.
G.
Chemical Name ...................................................................................................................................................8
Chemical Structure ..............................................................................................................................................9
Stereoisomers ......................................................................................................................................................9
Synthesis ..............................................................................................................................................................9
Chemical description...........................................................................................................................................9
Chemical properties ..........................................................................................................................................10
Chemical identification .....................................................................................................................................10
3.
Ease of convertibility into controlled substances .................................................................................................10
4.
General pharmacology ............................................................................................................................................10
4.1. Pharmacodynamics ...........................................................................................................................................10
4.2. Routes of administration and dosage................................................................................................................15
4.3. Pharmacokinetics ..............................................................................................................................................15
5.
Toxicology .................................................................................................................................................................17
6.
Adverse reactions in humans ..................................................................................................................................17
7.
Dependence potential ...............................................................................................................................................19
8.
Abuse potential .........................................................................................................................................................20
9.
Therapeutic applications and extent of therapeutic use and epidemiology of medical use ............................22
10. Listing on the WHO Model List of Essential Medicines .....................................................................................22
11. Marketing authorizations (as a medicine) ............................................................................................................22
12. Industrial use ............................................................................................................................................................22
13. Non-medical use, abuse and dependence ..............................................................................................................22
14. Nature and magnitude of public health problems related to misuse, abuse and dependence ........................24
15. Licit production, consumption and international trade ......................................................................................26
16. Illicit manufacture and traffic and related information .....................................................................................26
17. Current international controls and their impact .................................................................................................26
18. Current and past national controls ........................................................................................................................26
19. Other medical and scientific matters relevant for a recommendation on the scheduling of the
substance ...................................................................................................................................................................26
References ..........................................................................................................................................................................27
Annex 1: Report on WHO Questionnaire for Review of Psychoactive Substances for the 36th ECDD:
Evaluation of Mephedrone......................................................................................................................................31
Page 5 of 34 36th ECDD (2014) Agenda item 4.12 Page 6 of 34 Mephedrone 36th ECDD (2014) Agenda item 4.12 Mephedrone Summary Mephedrone (4-methylmethcathinone) is a synthetic cathinone. Mephedrone has never been
licensed as a medicine, also no other legitimate uses are known. Although new on the market
of recreational substances the history of mephedrone goes back to 1929 when its synthesis
was published.
The product started its way on the market around the time when the availability of 3,4methylenedioxymethylamphetamine decreased. Use of mephedrone was first reported around
2007 and since then increasing especially in Europe. This has led to a risk assessment by the
EMCDDA in 2010 (EMCDDA, 2011). Meanwhile use/abuse has also been reported from
Australia and the USA.
The effects and the mode of use reported have similarities with (meth)amphetamine, cocaine
and 3,4-methylenedioxymethylamphetamine, but its potency is less than (meth)amphetamine.
The overall profile shows a molecule with unique pharmacological properties. Not a new kid
on the block, nevertheless the study into its pharmacology and toxicology started only
recently.
Reported toxic effects of mephedrone include soar nose/nosebleeds after snorting,
tachycardia, hypertension, agitation, paranoia, hallucinations and insomnia. Some of these
effects leeding to hospital admissions. A number of analytically confirmed drug-related
deaths have been reported.
Animal studies have indicated that mephedrone possesses an abuse or dependence potential
but there are no human clinical studies to support this. There are reports to suggest that some
individuals with a particularly high dose and/or frequent use of mephedrone develop
significant ‘cravings’ for it. There is one confirmed report of mephedrone dependence in a
patient from Scotland.
Page 7 of 34 36th ECDD (2014) Agenda item 4.12 Mephedrone 1. Substance identification A. International Nonproprietary Name (INN)
Not applicable.
B. Chemical Abstract Service (CAS) Registry Number
1189805-46-6 (base)
1189726-22-4 (hydrochloride salt)
C. Other Names
Mephedrone, 4-methylmethcathinone, N-methylephedrone,
β-keto-(4,N-dimethylamphetamine), 4,N-dimethylcathinone,
p-methyl-methcathinone, 2-aminomethyl-1-tolyl-propan-1-one.
D. Trade Names
None.
E. Street Names
A number of street names for mephedrone can be found in the literature, like:
bubbles, blow, Charge+, Cristal bath, Crush, Dark+, doves, kata, Fisk, Fiskrens,
Flower Magic Powder, Flower Power, kati, Ketones, krabba, Kräfta, Lax, mef,
Meffe, mefi, Mefko, mefó, mephisto, miaow miaow, meow meow, miaou miaou,
Magic, MMC Hammer, moonshine, plant feeder, plant food, Räka, Real
Euphoria, Recharge, Rocket fuel. Rush, Special Diamond, Special Gold, Special
Original, Star Dust, Subcoca-1, top cat, Tornado, Torsk, Volt, White Gold, White
Aroma Crystals, zsuzsi ronzio.
F. Physical properties
The base is a yellowish liquid at ambient temperature.
Mephedrone hydrochloride salt is a white or lightly coloured powder.
G. WHO Review History
Mepehdrone was not previously pre-reviewed or critically reviewed. A direct
critical review is proposed based on information brought to WHO’s attention that
Mephedrone is clandestinely manufactured, of especially serious risk to public
health and society, and of no recognized therapeutic use by any party. Preliminary
data collected from literature and different countries indicated that this substance
may cause substantial harm and that it has no medical use.
2. Chemistry A. Chemical Name
IUPAC Name: (RS)-2-methylamino-1-(4-methylphenyl)propan-1-one
CA Index Name:
Mephedrone
Page 8 of 34 36th ECDD (2014) Agenda item 4.12 Mephedrone B. Chemical Structure
Free base:
Molecular Formula:
Molecular Weight:
Melting point:
Boiling point:
C11H15NO
177.242 g/mol
66.61° C
269.51° C
C. Stereoisomers
Mephedrone contains a chiral centre at the C-2 carbon of the propane sidechain,
so that two enantiomers exist: R-mephedrone and S-mephedrone.
Due to the similarity with cathinone the S form is thought to be more potent than
the R form.
D. Synthesis
The synthesis of mephedrone, mentioned as ‘toluyl-alpha-monomethylaminoethylcetone’, was first described by Saem de Burnaga Sanchez (1929). The
main synthetic route involves α-bromination of 4-methylpropiophenone followed
by reaction of the resulting compound (4-methyl-2-bromopropiophenone) with
methylamine hydrochloride and triethylamine in an acidic scavenger to produce 4methylmethcathinone. The reaction is then quenched with gaseous or aqueous
hydrogen chloride providing the hydrochloride salt that needs to be recrystallised.
The resulting product is always racemic.
There is the potential for other synthetic routes including oxidation of the
substituted ephedrine analogue (4-methylephedrine) with potassium permanganate
or potassium dichromate in a solution of diluted sulphuric acid. The precursor can
be obtained in a specific enantiomeric form, ensuring that the synthesis is stereoselective.
Alternative synthetic methods, though more cumbersome, have been described in
the literature such as the Hartung-Munch procedure.
E. Chemical description
Mephedrone (4-methylmethcathinone) is a beta-keto-amphetamine related to
cathinone and methcathinone.
Page 9 of 34 36th ECDD (2014) Agenda item 4.12 Mephedrone F. Chemical properties
The base is a yellowish liquid at ambient temperature.
Mephedrone hydrochloride salt is a white or lightly coloured powder. The powder
is readily soluble in water and therefore can be dissolved prior to oral/ rectal use
or injection.
G. Chemical identification
Gas-chromatography mass-spectrometry (GC-MS) and liquid chromatography
with mass spectrometry-mass spectrometry (LC-MS/MS) techniques have been
developed for the detection of mephedrone (Camilleri et al., 2010, Meyer et al.,
2010, Gibbons and Zloh, 2010). The mass-spectrometry technique does not
distinguish between the various methyl-methcathinone isomers. However, nuclear
magnetic resonance spectroscopy allow the isomers to be differentiated.
Mass spectral data for mephedrone (m/z): 58 (base peak, 100 %).
Mephedrone does not give a colour reaction with the Marquis test.
3. Ease of convertibility into controlled substances Mephedrone is not converted into controlled substances.
4. General pharmacology In 2014 mephedrone will celebrate its 85th anniversary. But its pharmacology and
toxicology
have
only
recently
been investigated. Mephedrone (4methylmethcathinone) is a β-ketoamphetamine stimulant drug of abuse with structural
and mechanistic similarities to methamphetamine.
4.1.
Pharmacodynamics
Biochemical effects
Martínez-Clemente et al., (2012) were one of the first to start investigations into the
pharmacological targets of mephedrone in rats to establish the basis of the mechanism
of action of this drug. They performed several in vitro experiments studying the effect
of mephedrone on monoamine uptake and the displacement of several specific
radioligands. In isolated synaptosomes from rat cortex or striatum, mephedrone
inhibited the uptake of serotonin (5-HT) with an IC50 value lower than that of
dopamine (DA) uptake (IC50=0.31±0.08 and 0.97±0.0 5μM, respectively). Moreover,
mephedrone displaced competitively both [³H]paroxetine and [³H]WIN35428 binding
in a concentration-dependent manner (Ki values of 17.55±0.78μM and 1.53±0.47 μM,
respectively), indicating a greater affinity for DA than for 5-HT membrane
transporters. The affinity profile of mephedrone for the 5-HT2 and D2 receptors was
assessed by studying [³H]ketanserin and [³H] raclopride binding in rat membranes.
Mephedrone showed a greater affinity for the 5-HT2 than for the D2 receptors.
In vitro studies using recombinant human monoamine transporters point in the same
direction (Eshleman et al., 2013). Mephedrone and methylone had higher inhibitory
potency at uptake compared to binding and generally induced release of preloaded
Page 10 of 34 36th ECDD (2014) Agenda item 4.12 Mephedrone [³H]neurotransmitter from human dopamine (hDAT), serotonin (hSERT) and
norepinephrine (hNET) transporters (highest potency at hNET), and thus are
transporter
substrates,
similar
to
methamphetamine
and
3,4
methylenedioxymetamphetamine. In general these substituted methcathinones had
low uptake inhibitory potency and low efficacy at inducing release via human
vesicular monoamine transporters (hVMAT2). Furthermore these compounds were
low potency h5-HT(1A) receptor partial agonists, h5-HT(2A) receptor antagonists,
weak h5-HT(2C) receptor antagonists and have no affinity for dopamine receptors.
The primary mechanisms of action may be as inhibitors or substrates of DAT, SERT
and NET.
Also in vivo methods employed by Baumann et al., (2012) showed similar results.
Due to its numerous mechanistic overlaps with methamphetamine and the cathinone
derivatives Angoa-Pérez et al., (2012) decided to start a study into the neurotoxicity of
mephedrone. They treated mice with a binge-like regimen of mephedrone (4 × 20 or
40 mg/kg) and examined the striatum for evidence of neurotoxicity 2 or 7 days after
treatment. Although mephedrone caused hyperthermia and locomotor stimulation, it
did not lower striatal levels of dopamine, tyrosine hydroxylase or the dopamine
transporter under any of the treatment conditions used. Furthermore, mephedrone did
not cause microglial activation in striatum nor did it increase glial fibrillary acidic
protein levels. These results strongly suggest that mephedrone does not cause
neurotoxicity to dopamine nerve endings of the striatum.
One of the most powerful actions associated with mephedrone is the ability to
stimulate dopamine (DA) release and block its re-uptake through its interaction with
the dopamine transporter (DAT). Although mephedrone does not cause toxicity to DA
nerve endings, its ability to serve as a DAT blocker could provide protection against
methamphetamine-induced neurotoxicity like other DAT inhibitors.
To test this possibility, Angoa-Pérez et al., (2013a) treated mice with mephedrone (10,
20, or 40 mg/kg) prior to each injection of a neurotoxic regimen of methamphetamine
(four injections of 2.5 or 5.0 mg/kg at 2 h intervals). The integrity of DA nerve
endings of the striatum was assessed through measures of DA, DAT, and tyrosine
hydroxylase levels. The moderate to severe DA toxicity associated with the different
doses of methamphetamine was not prevented by any dose of mephedrone but was
significantly enhanced. Mephedrone also enhanced the neurotoxic effects of
amphetamine and 3,4-methylenedioxymethamphetamine on DA nerve endings. In
contrast, nomifensine protected against methamphetamine-induced neurotoxicity. As
mephedrone increases methamphetamine neurotoxicity, the present results suggest that
it interacts with the DAT in a manner unlike that of other typical DAT inhibitors.
The effects of mephedrone on serotonin (5HT) nerve endings are not fully understood,
with some investigators reporting damage while others conclude it does not. Therefor
Angoa-Pérez et al., (2013b) performed another study to investigate if mephedrone
given alone or with methamphetamine or MDMA damages 5HT nerve endings of the
hippocampus.
The status of 5HT nerve endings in the hippocampus of female C57BL mice was
assessed through measures of 5HT, serotonin transporter (SERT) and tryptophan
hydroxylase 2 (TPH2). Mephedrone alone did not cause persistent reductions in the
Page 11 of 34 36th ECDD (2014) Agenda item 4.12 Mephedrone levels of 5HT, SERT or TPH2. Methamphetamine and MDMA alone caused mild
reductions in 5HT but did not change SERT and TPH2 levels. Combined treatment
with mephedrone and methamphetamine or MDMA did not change the status of 5HT
nerve endings to an extent that was different from either drug alone. Mephedrone does
not cause toxicity to 5HT nerve endings of the hippocampus. When co-administered
with methamphetamine or MDMA toxicity is not increased as is the case for dopamine
nerve endings when these drugs are taken together.
To summarize: mephedrone is a stimulant of dopamine release and blocks its reuptake through an its interaction with the dopamine transporter (DAT).
Furthermore it has some affinity for various serotonin receptor subtypes. And although
expected mephedrone does not have a neurotoxic effect on the dopamine or serotonin
system when given alone.
Functional effects
The cardiovascular effects of mephedrone were characterized in rats by Varner et al.
(2013). A group of 12 rats received radio telemetry probes which were used to
measure the changes in mean arterial pressure (MAP) and heart rate (HR).
Mephedrone was compared with metamphetamine. Mephedrone (0.01-9 mg/kg, i.v.)
elicited increases in MAP and HR that were very similar to those elicited by
methamphetamine (0.01-9 mg/kg, i.v.). The tachycardia and pressor responses to
mephedrone (3 mg/kg) were blocked by the β-blocker atenolol (1 mg/kg, i.v.) and the
α1, α2-blocker phentolamine (3 mg/kg, i.v.), respectively.
Repeated administrations of mephedrone (3.0 and 10.0 mg/kg, s.c., 3 doses) caused
hyperthermia but no long-term change in cortical or striatal amines, whereas similar
treatment with MDMA (2.5 and 7.5 mg/kg, s.c., 3 doses) evoked robust hyperthermia
and persistent depletion of cortical and striatal 5-HT (Baumann et al., 2012) .
Shortall et al., (2013a) examined the acute effects of several cathinones (cathinone,
methcathinone, mephedrone) on rectal and tail temperature of rats and compared it
with MDMA. In individually housed rats at normal room temperature, MDMA caused
sustained decreases in rectal and tail temperature. Mephedrone caused a transient
decrease in rectal temperature, which was enhanced by α(1) -adrenoceptor and
dopamine D(1) receptor blockade, and a prolonged decrease in tail temperature.
Cathinone and methcathinone caused sustained increases in rectal temperature.
To summarize: mephedrone has a pharmacological profile comparable to the other
amphetamine type stimulants but milder.
Behavioral effects
López-Arnau et al., (2012) recorded locomotor activity in mice following different
doses of cathinones (butylone, mephedrone and methylone).
All three cathinones (5-25 mg·/kg ) caused hyperlocomotion, which was prevented
with ketanserin or haloperidol. Mephedrone-induced hyperlocomotion was dependent
on endogenous 5-HT.
In this study mephedrone was found to be the cathinone derivative with highest
affinity for vesicular monoamine transporter-2 causing the inhibition of dopamine
uptake. The affinity of these three cathinones for 5-HT(2A) receptors was similar to
Page 12 of 34 36th ECDD (2014) Agenda item 4.12 Mephedrone that of MDMA. Vesicular content played a key role in the effect of mephedrone,
especially for 5-HT uptake inhibition. The potency of mephedrone in inhibiting
noradrenaline uptake suggests a sympathetic effect of this substance.
Den Hollander et al., (2013) treated mice with a binge-like regimen of mephedrone
(30 mg/kg, twice daily for 4 days) in order to investigate the possible long-term effects
of this drugs on a range of behavioral tests. Starting 2 weeks later, they performed
behavioral tests of memory, anxiety and depression. Mephedrone reduced working
memory performance in the T-maze spontaneous alternation task.
Shortall et al., (2013b) studied the behavioral effects of mephedrone in rats. Youngadult male Lister hooded rats received i.p. cathinone (1 or 4 mg/kg), mephedrone (1, 4
or 10mg/kg) or MDMA (10mg/kg) on two consecutive days weekly for 3 weeks.
Locomotor activity (LMA), novel object discrimination (NOD) and conditioned
emotional response (CER) were measured following intermittent drug administration.
Cathinone (1, 4 mg/kg), mephedrone (10mg/kg) and MDMA (10mg/kg) induced
hyperactivity following the first and sixth injections and sensitization to cathinone and
mephedrone occurred with chronic dosing. All drugs used impaired NOD and
mephedrone (10mg/kg) reduced freezing in response to contextual re-exposure during
the CER retention trial. At the doses examined, mephedrone, cathinone, and MDMA
induced similar effects on behaviour and failed to induce neurotoxic damage when
administered intermittently over 3 weeks.
Huang et al., (2012) compared the relative locomotor stimulant effects of mephedrone
(MMC) (1-10 mg/kg, s.c.) and 3,4-methylenedioxy pyrovalerone MDPV (0.5-5.6
mg/kg, s.c.) with d-methamphetamine (MA; 0.5-5.6 mg/kg, s.c.) and 3,4methylenedioxy methamphetamine
(MDMA) (1-7.5 mg/kg, s.c.). They used
locomotor activity (voluntary wheel running) as a model. The study was performed
with a group of eight male Wistar rats. Compared to counts of wheel rotations after
saline, a biphasic change in the pattern of counts was observed after injections of MA
and MDPV, with relatively higher counts following lower doses and lower counts
following the highest dose. However, monophasic, dose-dependent reductions in
counts were observed in response to injections of MDMA and 4-MMC. Thus,
voluntary wheel running yielded the same categorical distinctions for these drugs as
did prior experiments testing the effects of these drugs on monoaminergic
neurotransmission.
Gregg et al., (2013) tested the hypothesis that prior mephedrone (MEPH) exposure
enhances the locomotor-stimulant effects of cocaine and methamphetamine (METH)
in rats. For cocaine experiments, rats were pretreated with saline, cocaine (15 mg/kg),
or MEPH (15 mg/kg) for 5 days and then injected with cocaine after 10 days of drug
absence. For METH experiments, rats were pretreated with saline, METH (2 mg/kg),
or MEPH (15 mg/kg) and then injected with METH after 10 days of drug absence.
Cocaine challenge produced greater locomotor activity after pretreatment with cocaine
or MEPH than after pretreatment with saline. METH challenge produced greater
locomotor activity after METH pretreatment than after saline pretreatment; however,
locomotor activity in rats pretreated with MEPH or saline and then challenged with
METH was not significantly different. The locomotor response to MEPH (15 mg/kg)
was not significantly affected by pretreatment with cocaine (15 mg/kg) or METH (0.5,
2 mg/kg). The present findings that cocaine-induced locomotor activation is enhanced
by prior MEPH exposure suggests that MEPH cross-sensitizes to cocaine and
Page 13 of 34 36th ECDD (2014) Agenda item 4.12 Mephedrone increases cocaine efficacy. Interestingly, MEPH cross-sensitization was not
bidirectional and did not extend to METH, suggesting that the phenomenon is
sensitive to specific psychostimulants.
After intranasal mephedrone use humans have reported psychomotor speed
improvement suggestive of classic stimulant properties. Limitations of the user group
(which was impaired on some tasks) prompted Wright et al. (2012) to perform a
controlled laboratory investigation. They trained adult male rhesus monkeys to
perform tasks from the non-human primate Cambridge Neuropsychological Test
Automated Battery, which assess spatial working memory, visuospatial associative
memory, learning. Also a test of bimanual motor coordination and manual tracking
were included. The subjects were challenged with 0.178-0.56 mg·kg(-1) mephedrone
and 0.056-0.56 mg·kg(-1) d-methamphetamine, i.m. A pronounced improvement in
visuospatial memory and learning was observed after the 0.32 mg·kg(-1) dose of each
compound, this effect was confirmed with subsequent repetition of these conditions.
Spatial working memory was not improved by either drug, and the progressive ratio,
bimanual motor and rotating turntable tasks were all disrupted in a dose-dependent
manner.
To summarize: mephedrone has a behavioral profile comparable to other amphetamine
type stimulants but with some distinct differences.
Effects on cognition and behavior in humans
Herzig et al., (2013) investigated the acute and chronic effects of mephedrone
consumption on drug-sensitive cognitive measures. Volunteers from the general
population (n=26) performed several tasks measuring verbal learning, verbal fluency
and cognitive flexibility. Measuring was done before and after a potential drug-taking
situation (pre-clubbing and post-clubbing at dance clubs, respectively).The
participants also provided information on chronic and recent drug use, schizotypal
(Oxford-Liverpool Inventory of Feelings and Experiences) and depressive symptoms
(Beck Depression Inventory). Mephedrone users performed worse than non-users preclubbing and deteriorated from the pre-clubbing to the post-clubbing assessment. Postclubbing depression scores predicted relative cognitive attenuations. And schizotypy
was largely unrelated to cognitive functioning, apart from a negative relationship
between cognitive disorganisation and verbal fluency. Results suggest that polydrug
use and depressive symptoms in the general population negatively affect cognition.
Another study in humans by Freeman et al., (2012) aimed to assess the acute cognitive
and subjective effects of mephedrone use.
A mixed within- and between-subjects design compared 20 mephedrone users with 20
controls twice. The mephedrone users first while intoxicated (T1) and secondly drug
free (T2); and the controls twice when drug free (T1 and T2). All were healthy adults
recruited from the community and place of study was participants' own homes.
Subjective effects, episodic and working memory, phonological and semantic fluency,
psychomotor speed and executive control at were assessed at T1 and T2. Trait
schizotypy, depression and changes in mephedrone use since the ban were indexed at
T2 only. Compared with controls, mephedrone users had generally impaired prose
recall (P = 0.037) and higher scores in schizotypy (P < 0.001) and depression (P =
0.01). Mephedrone acutely primed a marked 'wanting' for the drug (P < 0.001),
induced stimulant-like effects, impaired working memory (P < 0.001) and enhanced
Page 14 of 34 36th ECDD (2014) Agenda item 4.12 Mephedrone psychomotor speed (P = 0.024). Impulsivity in mephedrone users correlated with the
number of hours in an average (nearly 8 hour) mephedrone session (r = 0.6).
Mephedrone impairs working memory acutely, induces stimulant-like effects in users
and is associated with binge use.
4.2.
Routes of administration and dosage
Mephedrone is used by the oral route, nasal insufflation, intramuscular injection,
intravenous injection and rectal insertion. And there are numerous reports of
individuals using mixed routes during a single session (oral and nasal, oral and rectal)
(EMCDDA, 2011).
The predominant routes are oral ingestion and nasal insufflation. According to the
MixMag survey, 70 % of users use mephedrone by nasal insufflation and 30 % by oral
ingestion (Dick and Torrance, 2010).
Swallowing took one of two forms: ‘bombing’ (wrapping a dose of powder in a paper
wrap (Measham et al., 2010)) or drinking (mixing the powder into a beverage, and
drinking it quickly). Mephedrone powder is usually sniffed or swallowed. Sniffing
mainly took the forms of ‘keying it’: sticking a key into the bag of powder, piling up
some powder on the thin end of the key, and then holding the key under a nostril and
sniffing vigorously. Many users reported switching from sniffing to swallowing
mephedrone, mainly because of its painful effects on the nasal membranes.
4.3.
Pharmacokinetics
Martínez-Clemente et al. (2013) investigated the pharmacokinetics of mephedrone in
rats. In order to provide a pharmacokinetic/pharmacodynamic model they also looked
at the locomotor activity of the animals.
Mephedrone was administered to male Sprague-Dawley rats intravenously (10 mg/kg)
and orally (30 and 60 mg/kg). Plasma concentrations and metabolites were
characterized using LC/MS and LC-MS/MS fragmentation patterns. Locomotor
activity was monitored for 180-240 min.
The plasma concentrations after i.v. administration fit a two-compartment model.
After oral administration, peak concentrations were achieved between 0.5 and 1 h and
declined to undetectable levels at 9 h. The absolute bioavailability of mephedrone was
about 10% and the percentage of mephedrone protein binding was 21.59 ± 3.67%.
They identified five phase I metabolites in rat blood after oral administration. The
relationship between brain levels and free plasma concentration was 1.85 ± 0.08.
Mephedrone induced a dose-dependent increase in locomotor activity, which lasted up
to 2 h. The pharmacokinetic-pharmacodynamic model successfully describes the
relationship between mephedrone plasma concentrations and its psychostimulant
effect.
Metabolites of mephedrone have been described earlier by Meyer et al. (2010). They
administered a single 20 mg/kg dose of mephedrone by gastric intubation to rats and
collected the urine over a 24-hour period after administration. Besides mephedrone,
the following metabolites were detected: nor-mephedrone, nor-dihydro mephedrone,
hydroxytolyl mephedrone and nor-hydroxytolyl mephedrone.
Page 15 of 34 36th ECDD (2014) Agenda item 4.12 Mephedrone In addition a urine sample submitted by a mephedrone user was analysed, and a
further metabolite, 4-carboxy-dihydro mephedrone was also detected.
The following overlapping metabolic pathways were postulated:
-
N-demethylation to the primary amine (metabolites nor-mephedrone, nor-dihydro
mephedrone and nor-hydroxytolyl mephedrone);
-
reduction of the keto moiety to the respective alcohol (metabolites nor-dihydro
mephedrone and 4-carboxy-dihydro mephedrone);
-
oxidation of the tolyl moiety to the corresponding alcohol (metabolites
hydroxytolyl mephedrone and nor-hydroxytolyl mephedrone).
It is thought that the hydroxytolyl mephedrone and nor-hydroxytolyl mephedrone
metabolites are partly excreted as glucuronides and sulphates.
Pedersen et al., (2013) showed that cytochrome P450 2D6 (CYP2D6) was the main
responsible enzyme for the in vitro Phase I metabolism of mephedrone, with some
minor contribution from other NAPDH-dependent enzymes.
In addition they did forensic casework on four traffic cases in which mephedrone was
detected. They identified hydroxytolyl-mephedrone and nor-mephedrone, as well as 4carboxy-dihydro-mephedrone. Also two new metabolites were identified, dihydromephedrone and 4-carboxy-mephedrone.
Other forensic casework has been performed by Cosbey et al. (2013). Analysis of
blood samples for mephedrone was conducted by liquid chromatography-mass
spectrometry. Mephedrone was detected in a total of 12 fatal cases. Most of these
cases involved death by mechanical means; however in two cases, death was attributed
directly to mephedrone intoxication (blood concentrations of 2.1 and 1.94 mg/L). In
32 impaired driving cases mephedrone was detected. Blood concentrations ranged up
to 0.74 mg/L (mean 0.21, median 0.10).
Although not common, mephedrone may also be ingested by vaporization/inhalation.
Therefor Kavanagh et al., (2013) examined the pyrolysis products produced by
heating mephedrone under simulated 'meth pipe' conditions. Thirteen pyrolysis
products were identified. The major ones being iso-mephedrone, 4methylpropiophenone, 4-methylphenylacetone, two pyrazine derivatives (formed by
dimerization of mephedrone), N-methylated mephedrone (N,N,4-trimethylcathinone),
two hydroxylated oxidation products and a diketone. Other minor products formed
were identified as 4-methylacetophenone, two α-chloro ketones and N-methylated isomephedrone.
The results of this study clearly show that one should not only look for known
metabolites when screening for the use of abused substances but also for other
products that might have been formed during (co)administration.
Mephedrone is reported to be used in single doses that vary from 15 to 250 mg for oral
ingestion and 5 to 125 mg for nasal insufflation, although due to short-lived effects the
total doses used per session may be greater, possibly between 0.5–2 g. Onset of
desired effects is typically seen within 15–45 minutes of oral ingestion. There are
some reports of slower onset of action when mephedrone is taken orally on a full
stomach. After nasal insufflation onset is reported by users to be within a few minutes
and with peak desired effects within 30 minutes. Users report that the desired effects
Page 16 of 34 36th ECDD (2014) Agenda item 4.12 Mephedrone last approximately 2–3 hours and therefore that they may consume multiple doses
during a session to prolong the duration of the desired effects.
Reports from intravenous mephedrone users suggest that the high lasts approximately
10–15 minutes with an overall duration of desired effects of approximately 30 minutes
(EMCDDA, 2011).
5. Toxicology There are no published pre-clinical safety data available concerning the toxicity,
reproductive impact and carcinogenic/mutagenic potential of mephedrone.
6. Adverse reactions in humans Adverse events
For drugs of abuse there is no formal registration system for adverse events.
Information can be obtained by surveys, by searching on internetfora and by collecting
information from national poison information services (James et al. 2011).
The following adverse events of mephedrone use have been mentioned:
Cardiovascular System:
Palpitations, tachycardia, arrhythmias;
Hypertension;
Hot flushes.
Central Nervous System, neurological symptoms:
Headaches, light-headedness, dizziness;
Tremors, convulsions;
Loss of concentration, and memory loss.
Central Nervous System, psychiatric symptoms:
Agitation, aggression;
Paranoia, hallucinations;
Insomnia, nightmares;
Anxiety, dysphoria, (post-use) depression;
Craving, addiction, dependence.
Central Nervous System, miscellaneous symptoms:
Increased or decrease in mean body temperature;
Dilated pupils, blurred vision.
Fatigue, loss of appetite.
Gastro-intestinal system:
Sore mouth/throat;
Abdominal pain;
Nausea, vomiting.
Musculoskeletal system:
Bruxism (teeth grinding);
Painful joints.
Page 17 of 34 36th ECDD (2014) Agenda item 4.12 Mephedrone Respiratory system:
Chest pain, respiratory difficulties.
Skin:
Skin rash, sweating.
Discoloration of extremities/joints.
In addition, nasal insufflation of mephedrone is reported to be associated with
significant nasal irritation and pain which has led to some users switching to oral use
of mephedrone.
Serious adverse events
The pharmacological and toxicological profile of mephedrone is quite similar to that
of other stimulant drugs of abuse like amphetamines, cathinones and cocaine.
But besides the expected adverse events also some other quite unexpected ones have
been presented in publications.
To give an overview: reversible dilated cardiomyopathy (Sivagnanam et al., 2013),
methaemoglobinaemia (Ahmed et al. 2010), pneumomediastinum (McCullough et al.,
2013), acute kidney injury (Rhidian and Babu, 2013), urinary retention (Conway et al.,
2013), subcutaneous emphysema (Maan and D’Souza 2012), posterior reversible
encephalopathy syndrome (Omer and Doherty 2011).
Non-fatal intoxications
Wood et al. (2010) were the first to describe a series of seven analytically confirmed
mephedrone-related acute intoxications.The presentated cases had clinical signs of
toxicity consistent with an acute sympathomimetic toxidrome (e.g. hypertension,
tachycardia and agitation). These findings are similar to the pattern of toxicity seen
with
other
sympathomimetic
recreational
drugs
such
as
3,4Methylenedioxymethamphetamine (MDMA) and cocaine. Acute mephedrone-related
toxicity was analytically confirmed in seven male patients; the mean ± SD age was
24.6 ± 6.5 years (range 16-36 years). Agitation (4 patients) was the most common sign
reported; other common symptoms included: palpitations (2 patients); chest pain (2
patients); self-limiting pre-hospital seizures (one patient) and headaches (one patient).
The mean heart rate was 109.1 ± 21.8 (range 80-140) beats per minute. The mean
systolic blood pressure was 153.0 ± 39.6 (range 110-210) mmHg.
Garrett and Sweeney (2010) describe a male patient with a clinical picture resembling
a serotonin synndrome. The patient had tachycardia, diaphoresis, hypertonia, hyperreflexia and clonus. Later on he became hyperthermic.
Fatal intoxications
The first death solely related to mephedrone was from Sweden (Gustavsson and
Escher, 2009). This was an 18-year old female with a reported use of mephedrone and
cannabis. She had an out of hospital cardio-respiratory arrest and was resuscitated in
the emergency department. 36 hours later she was declared brain-dead. Toxicological
screening of blood and urine revealed the presence of mephedrone only (unfortunately
the mephedrone concentration was not reported), with no other drugs or alcohol
detected.
Page 18 of 34 36th ECDD (2014) Agenda item 4.12 Mephedrone Since that time a number of fatal intoxications with mephedrone have been published.
For instance in the USA (Dickson et al., 2010), The Netherlands (Lusthof et al., 2011),
Italy (Aromatario et al., 2012), and Poland (Adamowicz et al., 2013).
The most extensive series has been reported by Schifano et al., (2012) from the UK.
This series is based on information from the UK National Programme on Substance
Abuse Deaths database. This database receives information from coroners on drugrelated deaths among both addicts and nonaddicts in the United Kingdom, the Channel
Islands, and the Isle of Man. The average annual response rate is 95%. The period of
reporting is September 2009-October 2011.
An in-depth analysis of this series reveiled the following.
In total 128 alleged mephedrone-associated fatalities have been reported. Mephedrone
was identified at postmortem in 90 cases; 62 of which were analyzed.
Typical mephedrone victims were young (mean age, 28.8 years), male, and with a
previous history of drug misuse.
Mephedrone alone was identified at postmortem on 8 occasions. In the other cases
mephedrone has been found in combination with one or more other substances, for
instance, alcohol (n=26), stimulants (n=22), hypnotics/tranquillizers (n=22) other new
psychoactive substances (piperazines, other cathinones, n=26).
Circumstances of death were: acute drug toxicity (n=26), self-inflicting harm (n=18.
Remarkable is the fact that in 11 cases the victims were found hanging), at-risk
behavior, for instance driving under the influence, (n=6).
7. Dependence potential Due to the resemblance of mephedrone with metamphetamine Motbey et al. (2013)
decided to compare the characteristics of intravenous mephedrone self-administration
in the rat. Intravenous self-administration is one of the established models to show
dependence or abuse liablity.
Methamphetamine was used as an active comparator. Male Sprague-Dawley rats were
trained to nose poke for intravenous mephedrone or metamphetamine in daily 2 h
sessions over a 10 d acquisition period. Dose-response functions were then established
under fixed- and progressive-ratio (FR and PR) schedules over three subsequent weeks
of testing. Results showed that mephedrone was readily and vigorously selfadministered via the intravenous route. Under a FR1 schedule, peak responding for
mephedrone was obtained at 0.1 mg/kg/infusion, versus 0.01 mg/kg/infusion for
metamphetamine. Break points under a PR schedule peaked at 1 mg/kg/infusion
mephedrone versus 0.3 mg/kg/infusion for methamphetamine. Final intakes of
mepehedrone were 31.3 mg/kg/d compared to 4 mg/kg/d for metamphetamine.
Two remarks should be made. Nose-poke based paradigms show higher levels of
responding than lever press studies. And methamphetamine in this study showed
weaker responses than usual. The low training dose might be the reason.
Page 19 of 34 36th ECDD (2014) Agenda item 4.12 Mephedrone They concluded that mephedrone supported high levels of self-administration,
matching or exceeding those previously reported with other drugs of abuse.
A similar kind of study was performed by Aarde et al. (2013), but they used the lever
press model. Groups of male Wistar and Sprague-Dawley rats were prepared with
intravenous catheters and trained to self-administer mephedrone in 1-hour sessions.
Per-infusion doses of 0.5 and 1.0 mg/kg were consistently self-administered, resulting
in greater than 80% discrimination for the drug-paired lever and mean intakes of about
2-3 mg/kg/hour. Dose-substitution studies after acquisition demonstrated that the
number of responses and/or the total amount of drug self-administered varied as a
function of dose. Their study confirmed the findings of Motbey et al.. In this
traditional pre-clinical self-administration model mephedrone clearly shows evidence
of stimulant-typical abuse liability.
Bajaj et al. (2010) presented a case of dependence and psychosis in a patient using
mephedrone. The patient needed inpatient hospital care, was treated with olanzapine
and recovered well.
Addiction/dependence symptoms were reported by 17.6 % of 205 mephedrone users in
a Scottish survey of school and college/university students (Dargan et al., 2010).
User reports suggest that some individuals with high/frequent use of mephedrone
develop a ‘craving’ for it (Measham et al., 2010); this could be due to the high
associated with its use and its relatively short duration of action. A report from
Slovenia suggests that many of the users consider craving to be the main problem
associated with mephedrone use. Users in this survey compared their experience with
cocaine, methamphetamine and speed and stated that they had not experienced similar
craving with these drugs.
These reports of mephedrone ‘dependence’ suggest that it is associated with
psychological rather than physical dependency similar to other stimulant drugs, such
as MDMA and cocaine.
8. Abuse potential Hadlock et al. (2011) studied the effects of repeated mephedrone injections (4× 10 or
25 mg/kg s.c. per injection, 2-h intervals, administered in a pattern used frequently to
mimic psychostimulant "binge" treatment). This results in a rapid decrease in striatal
dopamine and hippocampal serotonin transporter function. Mephedrone also inhibited
both synaptosomal dopamine and serotonine uptake.
The results were similar to the results found after methylenedioxymethamphetamine,
methamphetamine or methcathinone administration.
Like methylenedioxymethamphetamine, but unlike methamphetamine or
methcathinone, repeated mephedrone administrations also caused persistent
serotonergic, but not dopaminergic, deficits. However, mephedrone caused DA release
from a striatal suspension approaching that of methamphetamine and was selfadministered by rodents.
Page 20 of 34 36th ECDD (2014) Agenda item 4.12 Mephedrone Intracranial self-stimulation (ICSS) measures the behavioral effects of neuroactive
compounds on brain reward circuitry.
Robinson et al. (2012) investigated the ability of mephedrone and cocaine to alter
responding for electrical stimulation of the medial forebrain bundle in C57BL/6J mice.
Adult male mice (n=6) implanted with unipolar stimulating electrodes at the level of
the lateral hypothalamus responded for varying frequencies of brain stimulation
reward (BSR). The frequency that supported half maximal responding (EF50), the
BSR threshold (θ(0)), and the maximum response rate were determined before and
after intraperitoneal administration of saline, mephedrone (1.0, 3.0, or 10.0 mg/kg), or
cocaine (1.0, 3.0, or 10.0 mg/kg). Mephedrone dose-dependently decreased EF50
(max. effect=72.3% of baseline), θ(0) (max. effect=59.6% of baseline), and the
maximum response rate (max. effect=67.0% of baseline) beginning 15 min after
administration. Beginning immediately after administration, cocaine dose-dependently
lowered EF50 (max. effect=66.4% of baseline) and θ(0) (max. effect=60.1% of
baseline) but did not affect maximum response rate.
Bonano et al. (2014) examined the behavioral effects of (±)-methcathinone, (±)-3,4methylenedioxypyrovalerone
(MDPV),
(±)-3,4-methylenedioxymethcathinone
(methylone), and (±)-4-methylmethcathinone (mephedrone) in rats using intracranial
self-stimulation (ICSS). Male Sprague-Dawley rats with electrodes targeting the
medial forebrain bundle responded for multiple frequencies of brain stimulation and
were tested in two phases. First, dose-effect curves for methcathinone (0.1-1.0 mg/kg),
MDPV (0.32-3.2 mg/kg), methylone (1.0-10 mg/kg), and mephedrone (1.0-10 mg/kg)
were determined. Second, time courses were determined for effects produced by the
highest dose of each compound. Methcathinone produced dose- and time-dependent
facilitation of ICSS. MDPV, methylone, and mephedrone produced dose- and timedependent increases in low rates of ICSS maintained by low brain stimulation
frequencies, but also produced abuse-limiting depression of high ICSS rates
maintained by high brain stimulation frequencies. Efficacies to facilitate ICSS were
methcathinone ≥ MDPV ≥ methylone > mephedrone. Methcathinone was the most
potent compound, and MDPV was the longest acting compound.
Lisek et al. (2012) used motor activity and conditioned place preference (CPP) assays
to investigate behavioral effects of mephedrone. Acute mephedrone (3, 5, 10, 30
mg/kg, ip) administration increased ambulatory activity in rats. Mephedrone (5 mg/kg,
ip)-induced ambulation was inhibited by pretreatment with a dopamine D1 receptor
antagonist (SCH 23390) (0.5, 1, 2 mg/kg, ip) and enhanced by pretreatment with a
dopamine D2 receptor antagonist (sulpiride) (2 mg/kg, ip). Rats injected for 5 days
with low dose mephedrone (0.5 mg/kg, ip) and then challenged with mephedrone (0.5
mg/kg, ip) following 10 days of abstinence displayed sensitization of ambulatory
activity. In CPP experiments, mephedrone (30 mg/kg, ip) conditioning elicited a
preference shift in both rats and mice.
Taken together the data show that mephedrone has a unique pharmacological profile
with abuse liability. However, efficacies of compounds varied, with mephedrone
displaying the lowest efficacy to facilitate ICSS.
Page 21 of 34 36th ECDD (2014) Agenda item 4.12 Mephedrone 9. Therapeutic applications and extent of therapeutic use and epidemiology of medical use Not applicable.
10. Listing on the WHO Model List of Essential Medicines Mephedrone is not listed on the WHO Model List of Essential Medicines.
11. Marketing authorizations (as a medicine) Mephedrone has never been marketed as a medicinal product.
12. Industrial use Mephedrone has no industrial use.
13. Non‐medical use, abuse and dependence The information in this paragraph is a compilation of the EMCDDA report on
Mephedrone (2011) and some additional papers.
Mephedrone consumption has been identified in a range of sub-populations. In
addition to psychonauts (UK), mephedrone use has been identified in clubbing and
party milieu (France, UK, Netherlands, Slovenia), amongst school pupils (UK) and
gay men (France).
Mephedrone users are reported to be primarily male and aged between their late teens
and late-20s. The majority are recreational polydrug users, with alcohol, cannabis and
often cocaine, amphetamine and ecstasy in their drug using repertoire.
A typical mephedrone session
Intranasal use is by far the most used route of administration with doses being
administered every 30–60 minutes over the course of a session (typically 8–12 hours
in length) which may last several days in the case of some users! Although the average
consumption over a session is approximately 1 g, there are sub-groups of heavier users
who report consuming far more (maximum reported session was 16 g).
On average, participants reported having been using for 6.1 months (SD = 3.1). All
participants reported using with others (a mean of 10 (SD = 7.9) other users). 83 %
administer the first dose of a session as a line of the drug, through the intranasal route
(79.0%), 9.9% reporting bombing and 11.1 % put it in a drink. The first administered
dose was estimated to be around 125 mg. Over the course of a mean typical session
(lasting 13.9 hours (SD = 16.59)) an average of 1.09 g was consumed, though the
range was huge (100–9000 mg). During a typical session quite a number of other
psychoactive substances were used, like drinking alcohol (82 %), cannabis (36%),
ketamine (35%), cocaine (26%), ecstasy (23%) GBL (2%) and amphetamine (1%).
Page 22 of 34 36th ECDD (2014) Agenda item 4.12 Mephedrone Participants estimated that the total amount used in their heaviest session ranged from
100 mg–16 g (median = 1.5 g; mode = 1 g). The estimated duration of a maximum
session varied widely between 1–192 hours with a median/mode of 12 hours. 47 %
reported that they had used for more than two days in a row, a median of three days
consecutive use was reported.
The reasons for continuing to use mephedrone included pleasure (wanting to repeat a
desirable fun experience) and developing a habit (craving and dependence). Many
participants stated that when they first tried mephedrone it was effective in fairly small
doses, equivalent to about 50 to 75 mg. But with regular use, even within the first
session, the amounts used soon escalated. All participants began as experimental
occasional users of mephedrone, but most had quickly progressed to regular
recreational use, with weekend use being the norm. Two persons reported that they
had been using on a near daily basis for the past six weeks. Though most participants
had become regular users of mephedrone, none explicitly indicated that they felt
dependent on it or that they had become daily users. Even so, though withdrawal
symptoms were not reported, craving and tolerance were clearly evident in the
experiences of most participants. Craving is considered to be the main problem with
mephedrone. Even the users with a lot of experience with other substances (cocaine,
methamphetamine, speed, etc.) emphasised that they have never experienced such
craving with any other substances and that craving was the main reason they used
more mephedrone than they planned.
Of particular interest is the data collected on mephedrone related problems and
dependence. The findings suggest that the drug has a high abuse liability with over 30
% of the sample reporting three or more DSM criteria of dependence and being
classified as dependent. Tolerance, loss of control, a strong urge to use and using
despite problems, predominate. The findings are consistent with the high abuse
liability reported in the Mixmag survey (Winstock, 2010, Winstock et al., 2011).
Van Hout and Bingham (2012) describe the abuse potential of mephedrone when used
by intravenous injection. Participants were aware of risks and safe injecting practises,
but compulsive re-injecting with excessive binge use over long periods of time was
common. Intense paranoia, violent behaviour and aggression and emergence of
Parkinson type symptomatologies were reported. Multi and serial drug injecting with
heroin was used in efforts to manage the intense rush and avoid unpleasant comedown.
González et al. (2013) looked at the pattern of use of new psychoactive substances in a
group of Spanish research chemical (RC) users. A total of 230 users participated. The
most frequent RC’s were hallucinogenic phenethylamines (2C-B 80.0%, 2C-I 39.6%)
and cathinones (methylone 40.1%, mephedrone 35.2%). The most frequent
combination of RC with other illegal drugs was with cannabis (68.6%).
There is a specific RC user profile with extensive knowledge and consumption of
substances, using different strategies to reduce risks associated to its consumption.
Kelly et al. (2013) report on the results of a field-based survey of 1740 patrons at
nightlife venues in New York City. Only 1.1% reported the use of mephedrone, while
8.2% reported use of synthetic cannabinoids. Gay and bisexual men reported higher
prevalence of mephedrone use. Latinos reported higher prevalence of synthetic
cannabinoid use. The findings suggest that the use of mephedrone among adults in US
Page 23 of 34 36th ECDD (2014) Agenda item 4.12 Mephedrone nightlife scenes remains relatively low in comparison with European nightlife scenes,
and is low relative to other drug use among young people within these scenes.
Legislative changes declined the use of mephedrone due to closure of headshops,
increased street prices and concerns around contamination. But a more serious
problem due to regulation of psychoactive substances is the emergence of new street
stimulant drugs often with less information available on pharmacology and toxicology.
Refer also Annex 1: Report on WHO questionnaire for review of psychoactive
substances
14. Nature and magnitude of public health problems related to misuse, abuse and dependence The information in this paragraph is a compilation of the EMCDDA report on
Mephedrone (2011) and some additional papers.
Due to the absence of epidemiological data on prevalence, user self-reports place
lifetime use of mephedrone at around 40 % amongst UK clubbers (33 % last month
use), (20 % amongst Scottish students) and 40 % amongst the Northern Irish
schoolchildren attending focus groups. French TREND reports describe use as
restricted to a small, primarily Parisian milieu.
UK (focus group Middlesbrough)
In Middlesbrough a focus group was asked about how common mephedrone use was.
The clear consensus was that ‘everyone is doing it’, presumably meaning most or all
of the local recreational drug users and/or clubbers. Many participants reported
switching from sniffing to swallowing mephedrone, mainly because of its painful
effects on the nasal membranes.
In addition, some participants reported having friends and associates who had become
daily users. The most common drugs used in the same session as mephedrone were
alcohol and skunk-cannabis.
UK (survey Scotland)
In a survey of over 1000 school and college/university students in Scotland 20.3 % of
those surveyed had used mephedrone on at least one occasion (Dargan et al., 2010). Of
these, 23.4 % reported that they had used mephedrone on one occasion only; however,
4.4 % reported use on a daily basis (particularly in those aged under 21 years of age).
UK (online survey)
Winstock et al. (2011) report on an online survey. About 600 persons gave contact
details. The current sample (>200 individuals) was drawn from members of this group,
who were identified as ever having used mephedrone and who had provided their
mobile telephone numbers.
Page 24 of 34 36th ECDD (2014) Agenda item 4.12 Mephedrone A total of 100 participants completed the questionnaire. Their lifetime use of other
stimulants was very high, with 96 % ever having used ecstasy and 92 % cocaine.
Participants were asked about the frequency and intensity of 28 typical stimulant and
empathogen drug effects (both positive and negative and physical and psychological).
Mephedrone’s predominant effect profile is that of a typical stimulant drug with
evidence of frequent sympathomimetic physical effects. The drug also appears to have
a quite marked pro-social profile with relatively infrequent adverse psychological
effects.
Participants were asked about how they felt during the next day or two after a session
by indicating how frequently each of a number of typical stimulant withdrawal
symptoms were experienced and their intensity.
Participants were also asked to rate each of the three drugs (mephedrone, cocaine and
ecstacy) across a range of broad descriptors; the ‘pleasurable high’ of the drug, the
‘negative effects of the drug when high’, the ‘strength of effect’ and the ‘urge to want
more of the drug when using’. Mephedrone scored very high in most of the subjective
effects.
The major findings are that mephedrone has an effect profile that is more similar
toecstasy than cocaine except for its shorter duration of action and its urge to use
which is more similar to cocaine. 30% of the sample group potentially met criteria for
DSM-IV dependence and there was evidence of a strong compulsion to use the drug.
France
In the second half of 2009 ethnographic reports of mephedrone came in from the
Parisian gay milieu, where it was being used as an alternative to other psychotropics
for its ecstasy-like effects. Information was collected from seven users presenting
mephedrone powder for testing. Three users presented the powder as MDMA, two as
amphetamine, one as ‘MPK’ and only one as mephedrone. All users were aged
between 25 and 30 and all described the drug’s effects as ecstasy-like or
amphetamine-like. In terms of route of use, four users sniffed the drug and three
swallowed. Quantities presented varied between 0.1 g and 0.25 g. The mephedrone
was taken in combination with alcohol (7 cases), cannabis (7 cases), cocaine (3 cases)
and heroin (1 case).
Netherlands
Information was gathered on the acute subjective effects of mephedrone from
interviews with 70 regular drug consumers in the second half of 2009.
60 users indicated that they anticipated effects of ecstasy, the rest were already
acquainted with mephedrone. The most frequently reported emotional effects were
euphoria, improved mood and craving (often reported as ‘redosing’ after a short
period) and the most frequently described somatic effects were increased energy and
accelerated heartbeat.
Page 25 of 34 36th ECDD (2014) Agenda item 4.12 Mephedrone Remarkable in all studies is that there is quite a high percentage of concomittant use of
other psychoactive susbatcnes, including ethanol. That makes it difficult to assess the
potential risks of mephedrone as such.
Refer also Annex 1: Report on WHO questionnaire for review of psychoactive
substances
15. Licit production, consumption and international trade There are no known uses of mephedrone as a research, industrial, agricultural or
cosmetic compound, despite it being marketed as ‘plant feeder’, ‘bath salts’ or
‘research chemical’.
Refer also Annex 1: Report on WHO questionnaire for review of psychoactive
substances.
16. Illicit manufacture and traffic and related information Refer Annex 1: Report on WHO questionnaire for review of psychoactive substances.
17. Current international controls and their impact Not applicable.
18. Current and past national controls Refer Annex 1: Report on WHO questionnaire for review of psychoactive substances.
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Page 29 of 34 36th ECDD (2014) Agenda item 4.12 Page 30 of 34 Mephedrone 36th ECDD (2014) Agenda item 4.12 Mephedrone Annex 1: Report on WHO Questionnaire for Review of Psychoactive Substances for the 36th ECDD: Evaluation of Mephedrone Data were obtained from 72 WHO Member States (18 AFR, 13 AMR, 5 EMR, 29 EUR,
3 SEAR, 4 WPR).
A total of 65 Member States answered the questionnaire for mephedrone; 4methylmethcathinone (4-MMC). Of these, only 34 respondents (AMR 5, EMR 1, EUR 23,
SEAR 1, WPR 4 ) had information on this substance.
LEGITIMATE USE
None reported that mephedrone was currently authorized or is in the process of being
authorized/registered as a medical product in their country. Five respondents stated that this
substance was used in research or as analytical standards. There was no use stated for
animal/veterinary care
HARMFUL USE
Twenty-one respondents confirmed that there was recreational/harmful use of mephedrone;
common routes of administration were stated as oral/ inhaling/sniffing by 7, oral by 4,
inhaling/sniffing by 4, injection/ inhaling/sniffing by 2, and oral/ injecting, inhaling/sniffing
by 2. Thirteen respondents stated that this is obtained via trafficking, 3 via diversion plus
trafficking, and 1 each via clandestine manufacturing and trafficking plus clandestine
manufacturing. Seventeen respondents reported on the common formulations of mephedrone
available with 8 reporting powder, 7 reporting powder/tablet and one each liquid and tablet
forms. When asked if mephedrone was used by any special populations 2 respondents stated
that it was used by the general population and in clubs, 3 only in clubs and 3 only in the
general population. Two respondents report overdose deaths in 2012, one and 32 deaths
respectively, the latter including deaths due to all cathinones. Two respondents report
emergency room visits of one and two respectively for 2012. In addition, one provided
emergency room visits data for 2012 and 2013 as 6 and 10 respectively. Nine respondents
reported withdrawal, tolerance and other adverse effects or medical illnesses caused by
mephedrone. These included nasal irritation secondary to insufflation, pupil dilation, sweating
and chills, hyperthermia, palpitations, tachycardia, hypertension, impaired memory,
restlessness, insomnia, trismus and bruxism, light headedness, agitation, spasm, tremor,
seizures, coma, blurred vision, hallucinations, psychosis, rhabdomyolysis, hyponatraemia and
vomiting. Reports also suggest potential for dependence such as desire to redose. Reports
also indicate that criminal groups are involved in the supply of mephedrone.
Additional information include ‘a survey of college students in 2012 by the Monitoring the
Future (MTF) showed that 0.2% of full-time college students used synthetic cathinone
substances. The use of synthetic cathinone substances among 8th, 10th, and 12th grade
students and young adults (non-college peers aged 19 to 28-years-old) was 0.8%, 0.6%, 1.3%,
and 0.8%, respectively. According to a press release from the American Association of Poison
Control Centers (AAPCC), there were 306 exposure calls related to synthetic cathinones in
2010, 6,137 calls in 2011, and 2,691 calls in 2012. According to the 2010 annual report of the
American Association of Poison Control Centers, (AAPC) “bath salts” are an emerging drug
Page 31 of 34 36th ECDD (2014) Agenda item 4.12 Mephedrone of concern, with the Center receiving a peak of approximately 40 calls per day between April
and July 2011 (Bronstein et al. 2011). Another AAPC update reported receiving 6,138 calls
related to “bath salts” in 2011 (AAPC 2012). It is unknown whether these calls were due to
mephedrone specifically, although mephedrone has been positively identified in over-thecounter samples of “bath salts”. The majority of reports documenting behavioral effects and
overdose with mephedrone or its analogues are case reports and media reports. These reports
describe a wide variety of adverse effects typical of stimulant-like drugs (MMWR 2011)
including hallucinations (Penders and Gestring 2011), paranoid psychosis (Antonowicz et al.
2011), delirium (Kasick et al. 2012), and death (Murray et al. 2012). Some of these case
reports are based upon the consumption of “bath salts” so a direct link to mephedrone cannot
be made. However, mephedrone has been confirmed in biological samples obtained from
patients hospitalized after ingesting bath salts (Dickson et al. 2010;Lusthof et al.
2011;Maskell et al. 2011;Torrance and Cooper 2010;Wood et al. 2010a;Wood et al. 2010b).’
‘Kapitány-Fövény et al. (2012) carried out a survey among 135 mephedrone users in 2011.
The questionnaire addressed the general characteristics of substance use, the circumstances of
the first use and the current use of mephedrone. Typically the first use of mephedrone took
place in recreational setting, at places of entertainment or in discos (56.3%), most typically
jointly with one or more friends (91.9%). The substance was typically obtained from a close
friend (48.9%) or acquaintance (34.1%), only a few respondents mentioned a person they did
not know (8.9%) or the internet (5.2%) as their source. The route of administration was
sniffing in the case of a significant proportion of the respondents 38 (85.2%) besides oral
administration (34.8%). Injecting use was mentioned by 12.3% of the respondents, i.e. 17
persons, 11 of whom said that injecting use was their only route of administration. Other
drugs used besides mephedrone were typically cannabis and amphetamines, opiate use was
not typical. The most common answers relating to the cause of drug use included
experiencing an altered state of consciousness (57.2%) and relaxation and recreation (41.2%).
The most typical answers describing the effect of the substances mentioned pleasant mood
(80.3%), light-heartedness (68.3%) and euphoria (68.2%). Two negative effects were
mentioned, such as lack of appetite (58.6%) and troubled sleep, insomnia (50.7%). 75.4% of
the respondents answered yes to the question whether mephedrone use caused dependence.’
CONTROL
Of those with information on this substance 32 reported that mephedrone was controlled
under legislation that was intended to regulate its availability; 28 under “controlled substance
act”, 1 under “medicines law” and 2 under “other” legislations. Only 5 respondents stated that
there were challenges with the implementation of this legislation. On illicit activities
involving mephedrone, two respondents reported clandestine manufacture and one the
synthesis of the product itself. Five respondents reported processing into the consumer
product, 16 reported trafficking, three reported diversion and 13 an internet market.
Details on seizures are presented below.
Total number of seizures
Total quantity seized (kg)
Total quantity seized (L)
Total quantity seized
(tablets/pills)
2011
(number of respondents)
547 (12)
292.02 (12)
4,051 (1)
8,755 (6)
Page 32 of 34 2012
(number of respondents)
227 (14)
308.56 (13)
2,855 (1)
716 (4)
36th ECDD (2014) Agenda item 4.12 Mephedrone Others seized
wraps, pieces, bags
Page 33 of 34 wraps, pieces, bags
36th ECDD (2014) Agenda item 4.12 Mephedrone IMPACT OF SCHEDULING
Twenty-nine respondents reported that if mephedrone was placed under international control,
they would have the laboratory capacity to identify the substance. It has no reported medical
use.
Page 34 of 34